CTP-Modified Coagulation Factors for Hemostasis

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Solution Overview

Problem

Current treatments for hemophilia, particularly Hemophilia B, face challenges in developing long-acting Factor VIIa with prolonged half-life while maintaining biological activity and avoiding immunogenicity, necessitating a solution that extends the duration of haemostatic activity and reduces the frequency of dosing.

Innovation Solution

A chorionic gonadotropin carboxy-terminal peptide (CTP)-modified coagulation factor is developed by attaching three CTPs to the carboxy terminus of Factor IX, Factor VII, or activated Factor VIIa, enhancing their half-life and potency, and administered via subcutaneous or intravenous routes to reduce bleeding and maintain hemostasis.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If recombinant FIX or FVIIa is administered to treat hemophilia, then bleeding control is improved, but the half-life is short requiring frequent dosing

Engineering Contradiction:

Improvebleeding controlVSAvoidhalf-life

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent creates a composite protein structure by fusing FVIIa or FIX with CTP from chorionic gonadotropin. This composite construct combines the hemostatic function of the coagulation factor with the long circulating half-life properties of the CTP, achieving both reliable bleeding control and extended duration of action

Inventive Principle:

Principle #40Composite materials

Solution Approach 2:

The invention merges two separate functional elements: the coagulation factor (FVIIa or FIX) responsible for hemostatic activity and the CTP responsible for prolonged circulation. This merging creates a single chimeric protein that inherits benefits from both components, eliminating the need for frequent dosing while maintaining effective bleeding control

Inventive Principle:

Principle #5Merging (Combining)

2Ease of operation

If the frequency of dosing is reduced to improve patient compliance, then treatment convenience is improved, but adequate hemostatic coverage may be compromised

Engineering Contradiction:

Improvedosing frequencyVSAvoidhemostatic coverage

Core Design Contradiction:

Ease of operationVSReliability

Solution Approach 1:

The patent dynamically adjusts the pharmacokinetic profile of the coagulation factor by attaching CTP, which extends the half-life from approximately 2.5-6 hours to potentially several days. This dynamic extension of circulation time allows for reduced dosing frequency (from multiple times daily to once weekly or less) while maintaining adequate hemostatic coverage throughout the extended period

Inventive Principle:

Principle #15Dynamics

3Duration of action of moving object

If protein modifications are made to prolong half-life, then duration of action is improved, but immunogenicity may increase

Engineering Contradiction:

Improvehalf-lifeVSAvoidimmunogenicity

Core Design Contradiction:

Duration of action of moving objectVSObject-affected harmful factors

Solution Approach 1:

The patent changes the molecular parameters of the coagulation factor by adding the CTP sequence, which alters the protein's pharmacokinetic properties including half-life and clearance rate. This parameter change achieves prolonged duration of action while the CTP sequence appears to maintain low immunogenicity, as it is derived from a human hormone that is naturally tolerated by the immune system

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentEP3326642B1Long-acting coagulation factors and uses thereof

Publication Date: 2020.11.25 OPKO BIOLOGICS LTD

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Figure 4~5C

AI summary

A chorionic gonadotropin carboxy terminal peptide (CTP)-modified Factor IX, Factor VII or Factor VIIa coagulation factor having three CTPs attached to the carboxy terminus of said coagulation factor for use in reducing excessive bleeding or bruising or for use in maintaining hemostasis during surgery or during surgical interventions in a subject.